Androstane derivatives

ABSTRACT

14A,17A - ALKYLIDENEDIOXY-AND 14A,17A - BENZYLIDENEDIOXY-ANDROSTANE-3-ONE COMPOUNDS HAVING A 11B-ACETOXY OR HALOGEN SUBSTITUENT ARE DISCLOSED. THE NEW COMPOUNDS POSSESS PROGESTATIONAL ACTIVITY.

United States Patent 3,585,191 ANDROSTANE DERIVATIVES Arthur F. Marx andHermanus J. Kooreman, Delft, Netherlands, assignors to KoninklijkeNederlandsche Gist-En Spiritusfabriek N.V., Delft, Province of SouthHolland, Netherlands No Drawing. Filed Sept. 9, 1969, Ser. No. 856,467Claims priority, application Great Britain, Sept. 11, 1968, 43,295/ 68Int. Cl. C07c 173/00 US. Cl. 260-23955 12 Claims ABSTRACT OF THEDISCLOSURE 140:,170: alkylidenedioxyand 140:,170:benzylidenedioxy-androstane-3-one compounds having a llfl-acetoxy orhalogen substituent are disclosed. The new compounds possessprogestational activity.

BACKGROUND OF THE INVENTION This invention relates to newtherapeutically useful steroids of the androstane series, to processesfor their preparation and to pharmaceutical compositions containingthem.

SUMMARY OF THE INVENTION New steroids have been discovered which are1404,1700- inethylenedioxy-androstane derivatives of the formulaDESCRIPTION OF THE PREFERRED I EMBODIMENTS The14a,17a-methylenedioxy-androstane derivatives of Formula 1 may beprepared by methods known per se for the preparation of analogouscompounds. By the term methods known per se is meant methods heretoforeused or described in the chemical literature.

According to a feature of the invention the androstane derivatives ofFormula 1, wherein R represents an acetoxy group, are prepared byreacting 14a,17a-dihydroxyprogesterone with an aldehyde of the formulaRCHO,

whereinR is as hereinbefore defined, followed by conice verting the thusobtained 14u,17o-methylenedioxy derivative of the formula v wherein R isas hereinbefore defined, to the corresponding -acetoxy-androstanederivative in manner known per se. The14a,l7a-methylenedioxy-progesterone derivatives of Formula 2 aredisclosed in our copending US. patent application Ser. No. 712,600 whichapplication is incorporated herein by reference.

Preferably the reaction of 14a,17a-dihydroxyprogesterone with analdehyde of the formula RCHO is carried out at room temperature in thepresence of a strong acid as catalyst and, if desired, in an inertorganic medium. Preferred catalysts are perchloric acid,p-toluenesulphonic acid, sulphuric acid and hydrochloric acid. Suitablesolvents include dioxane, tetrahydrofuran, benzene anddimethylforr'namide.

The conversion of a 14u,17a-methylenedioxyprogesterone derivative ofFormula 2 to the corresponding 173- acetoxy-androstane derivative ofFormula 1, is preferably carried out in five subsequent reaction steps.I

(a) Protection of the 3-keto group; this protection can be obtained forexample by reacting a progesterone derivative of Formula 2 with atrialkyl orthoformate of the formula (R O) CH, wherein R represents analkyl group having less than 5 carbon atoms, to give a 3'alkoxy- 14a,17amethylenedioxy 3,5 pregnadiene 20 onederivative of the formula wherein Rand R are as hereinbefore defined. The reaction is preferably carriedout in an inert organic solvent medium, such as dioxane, in the presenceof a' small amount of a strong acid, such as pto1uenesulphonic acid, atroom temperature. 7 Y

(b) A compound of Formula 3 is then converted with hydroxylamine to thecorresponding 20-oximino derivative of formula wherein R is ashereinbefore defined is obtained.

(d) A compound of Formula 5 then is subjected to a Beckmannrearrangement to prepare the corresponding 17/8-acetylamino-androstanederivative of the formula wherein R is as hereinbefore defined. Thereaction is preferably carried out with phosphorus oxychloride inpyridine at a temperature somewhat below room temperature, for example10 C.

(e) Finally, 17fl-acetylamino-androstane derivative of Formula 6, isconverted to the corresponding 17,8-acetoxyandrostane derivative ofFormula 1, wherein R is as hereinbefore defined and R represents anacetoxy group. The conversion can be effected with a nitrosating agent,such as nitrosyl chloride. The reaction is preferably carried out in anacetic acid and acetic anhydride containing medium in the presence ofpotassium acetate at a temperature somewhat below room temperature, forinstance 5-10 C.

All the compounds of Formulas 3, 4, 5 and 6 are new and particularlyuseful in a preferred procedure for preparing compounds of Formula 1 andform a feature of the invention.

According to another feature of the invention, it has been found thatthe androstane derivatives of Formula 1, wherein R represents a halogenatom and R is as hereinbefore defined, are prepared by reacting14a,l7oc-dlhydroxy-4-androsten-3-one-l7fl-carboxylic acid with analdehyde of the formula RCHO, wherein R is as hereinbefore defined,followed by converting the thus obtained 1401,1701.- methylenedioxyderivative of the formula 4 scribed above for the corresponding reactionwith 14a,17ocdihydroxyprogesterone.

The starting material in the above process, 1411,1701-dihydroxy-4-androsten-3-one-17B-carboxylic acid, may be prepared byoxidation of 14a,l7a,2l-trihydroxyprogesterone (14u,17x,21-trihydroxy-4-pregnene-3,20-dione). A suitable oxidation agent isfor example periodic acid (H 10 the reaction is carried out in an inertorganic medium, such as tetrahydrofuran, at room temperature.

A compound of Formula 7 is converted to the corresponding 17fl-haloderivative by means of a modified Hunsdiecker reaction (J. Org. Chem.1961, 26, 280). The reaction is carried out in the presence of leadtetraacetate and in a suitable organic solvent medium, such as benzeneor carbon tetrachloride. Chlorine can be provided in this reaction by,for example, lithium chloride; iodine is preferably added as such to thereaction mixture. In the preparation of the iodoandrostane derivativesthe reaction mixture is preferably illuminated with a tungsten lamp.

According to a modification of this procedure to prepare17,8-halo-androstane derivatives of Formula 1, first14a,l7a,2l-trihydroxyprogesterone is reacted with an aldehyde of theformula RCHO, wherein R is as hereinbefore defined, in the same manneras described above, to give the corresponding 14u,17u-methylenedioxyderivative. Preferably, the 21-hydroxyl group is protected, for exampleby converting it with acetic anhydride in pyridine to the 21-acetoxygroup, before carrying out the reaction with an aldehyde of the formulaROHO. After the introduction of the 14a,l7a-methylenedioxy group the 21-acetoxy group can then be converted again to the 21- hydroxy group, forexample by alcoholysis with sodium methanolate in methanol. There isobtained a 2l-hydroxyl4a1,17a-methylenedioxy progesterone derivative offormu a (ilHzOH 0:0

EXAMPLE I (a) To a solution of 20 g. of 14a,17a,2l-trihydroxy-4-pregnene-3,20-dione in a mixture of 300 ml. of tetrahydrofurane and 45ml. of water was added a solution of 19.5 g. of periodic acid (H IO in78 ml. of water at such a rate that the addition was completed in about15 minutes. The mixture was kept at 25 C. for 2.5 hours; then 280 ml. ofwater were added and the mixture was concentrated in vacuo. The crystalsformed were collected, washed with water and dried in vacuo. Yield: 17.5g. of 14a,17u-dihydroxy-4-androsten-3-one-17,3-carboxylic acid.

Melting point: ZOO-205 C. I.'R. (in KBr): v =3320, 2650, 2580, 1725,1660, 1619 and 1198 cm.-

(b) A solution of 1.0 g. of14a,l7u-dihydroxy-4-androsten-3-one-17fi-carboxylic acid in a mixture of6 ml. of

paraldehyde, 6 ml. of dioxane and 0.05 ml. of 70% perchloric acid waskept at room temperature for 4 hours. The mixture was neutralized with afew drops of pyridine; the steriod percipitated on addition of 30 m1. ofwater. Yield: 0.9 g. of 13a,17u-ethylidenedioxy-4-androsten-3-one-l7l8-carboxylic acid.

Melting point: 228-230 C. I.R. (in CHCI v =3435, 1770, 1708, 1664 and1614 cm.-

(c) A mixture of 4.0 g. of 14a,17a-ethylidenedioxy-4-androsten-3-one-17fl-carboxylic acid, 5.5 g. of lead tetraacetate, 0.46g. of lithium chloride and 130 ml. of benzene was refluxed undernitrogen for 30 minutes. The cooled mixture was diluted with 300 ml. ofmethyl isobutyl ketone, washed with water and the solvent evaporated invacuo to give a residue which was crystallized from methanol/water andthen from acetone. Yield: 0.85 g. of 173-chloro-14a,17a-ethylidenedioxy-4-androsten-3-one.

Melting point: l37-138 C.

A (in methanol)=240 nm.; E{" =470 I.R. (in CHCl v =l665, 1614, 1408 and1101 cm.- N.M.R. (in CDCl 6:1.07, 1.19, 1.36 (doublet), 5.19

(quadruplet and 5.74 p.p.m. Elementary analysis:

Calculated for C H O Cl (percent): C, 69.14; H, 7.96; Cl 9.74. Found(percent): C, 68.75; H, 7.92; C1 10.03.

EXAMPLE II (a) According to the procedure described in Example Ib,14cc,170l. dihydroxy-4-androsten-3-one-17,8-carboxylic acid (preparedaccording to the procedure of Example Ia) was converted with hexanal tol40c,l7ot-l16XyllClI1edlOXy- 4-androsten-3-one-17 8-carboxylic acid.

Melting point: 176l77 C. N.M.R. (in CD01 6:0.90 (triplet), 1.03, 1.22,5.03

(triplet) and 5.83 p.p.m.

(b) According to the procedure described in Example Ic, 140:,17ochexylidenedioxy 4-androsten-3-one-17,8-carboxylic acid was converted to17B-ch1oro-14a,17a-hexylidenedioxy-4-androsten-3-one, isolated as anoil.

LR. (in CHCl v =1665, 1613, 1160 and 1109 cm.- N.M.R. (in CDCl 6:0.87(triplet), 1.07, 1.20, 5.02

(triplet) and 5.77 p.p.m. Molecular ion peak in mass spectrum:

Calculated for C H O Cl: 420/422. Found: 420/ EXAMPLE III (a) Accordingto the procedure described in Example Ib, 1404,170:dihydroxy-4-androsten-3-one-17B-carboxyl1c acid (prepared according tothe procedure of Example Ia) was converted with benzaldehyde to14a,170c-b61'1Zylidenedioxy-4-androsten-3-one- 17 fl-carboxylic acid.

Melting Point: 247-248 C. N.M.R. (in C-DCl 6:1.10, 1.20, 5.77 and7.3-7.6

(multiplet) p.p.m.

(b) -According to the procedure described in Example Ic, 14ot,17ocbenzylidenedioxy-4-androsten-3-one-17,8-car: boxylic acid was convertedto 17B-chloro-l4a,17a-benzylidenedioxy-4-androsten-3-one, isolated as anoil.

A (in methanol): 240.5 nm.; E}Z' =390 LR. (in CHCl v =1668, 1615, 1092and 990 cmr N.M.R. (in CDCl :1.15, 1.20, 5.77, 6.02 and 7.3-

7.7 (multiplet) p.p.m. Highest mass numbers in mass spectrum:

Calculated for C H O Cl: 426/428. Found: 320/ 322 [according tomolecular weight 106 (:mol. weight C H ]CHO).

6 EXAMPLE IV (a) A solution of 25 g. of14m,l7a,21-trihydroxyprogesterone in a mixture of ml. of pyridine and 25ml. of acetic anhydride was kept at room temperature for 4 hours. Then150 ml. of water were added and the precipitate was collected, Washedwith water and dried in vacuum. Yield: 27.5 g. of14a,l7a-dihydroxy-2l-acetoxyprogesterone.

Melting point: 229-231 C. [.R. (in CHCl v =36l6, 3480, 1742, 1729, 1663,

1613 and 1373 cmf (b) A mixture of 27.5 g. of c,17u-dlhY(llOXY-21-acetoxyprogesterone, 100 ml. of paraldehyde, 200 m1. of methylenechloride and 2.5 ml. of 70% perchloric acid was agitated at roomtemperature for 15 minutes. Then the mixture was washed with a N aqueoussolution of sodium bircarbonate and with water. The organic layer wasevaporated to dryness in vacuo and the residue crystallized frommethanol. Yield: 23.7 g. of 14a,171-ethylidenedioxy-Zl-acetoxyprogesterone.

Melting point: 177-179 C. LR. (in CHCI 1 =1747, 1730, 1665, 1612, 1112and 1070 cmf (c) To a solution of 23.7 g. of14a,17u-ethylidenedioxy-2l-acetoxyprogesterone in a mixture of 100 ml.of methanol and 100 ml. of methylene chloride was added under nitrogen23 ml. of a N solution of sodium methanolate in methanol. The reactionmixture was stirred for 30 minutes under nitrogen at room temperatureand then neutralized with acetic acid. The mixture was evaporated todryness in vacuo and the residue crystallized from methanol/water.Yield: 12.7 g. of 21-hydroxy-l4a,17aethylidenedioxyprogesterone.

Melting point: 21 l-215 C.

LR. (in CHCl v =3505, 1715, 1668, 1618, 1113 and 1092 cmf Melting point:2275-229 C.

(e) To a stirred suspension of 4.43 of lead tetra-acetate in 75 ml. ofrefluxing carbon tetrachloride, were added 3.74 g. of14a,l7a-ethylidenedioxy-4-androsten-3-one-17B- carboxylic acid andthen 1. 27 g. of iodine. The reaction mixture was illuminated with atungsten lamp for 2 hours. The cooled reaction mixture was filtered andthe filtrate washed with N perchloric acid and water. On evaporation ofthe solvent a residue was obtained which crystallized from methanolyielding 1.0 g. of 17fl-l0d0-l4oz,l7otethylidenedioxy-4-androsten-3-one.

A... (in methanol)=241 nm.; E}? =315 I.R. (in CHlg): 11 zl668, 1612,1403 and 1099 cm. N.M.R. (in CDCl 6:1.01, 1.19, 1.30 (doublet). 5.20(quadruplet) and 5.73 p.p.m. Highest mass number in mass spectrum:

Calculated for C H O I: 456. Found: 285 [accord ing to molecularweight-171 (i.e. I+CH CHO); m/e=127 (1+) is also very abundant].

7 EXAMPLE v According to the procedure described in Example IVe,14a,17o-hexy1idenedioxy 4 androsten 3 one-17,8- carboxylic acid(prepared according to the procedure described in Example Ila) wasconverted to 17B-iodo- 14a,17a-hexylidenedioxy-4-androsten-3-one,isolated as an oil.

A (in methanol)=240.5 nm.; E}Z' =320 LR. (in CHCl 6 =166l, 1152, 1100,990, 940 and 862 CHI-1.

N.M.R. (in CDCl :0.98 (triplet), 1.08, 1.20, 5.01

(triplet) and 5.77 p.p.m.

Highest peak in mass spectrum:

Calculated for C H O I: 512. Found: 366 [according to molecularweight(128+18) (i.e. mol. weight HI+H O)].

EXAMPLE VI According to the procedure described in Example We, 14a,17a.benzylidenedioxy 4 androsten-3-one-17B-carboxylic acid (preparedaccording to the procedure described in Example IIIa) was converted to17/3-iodo- 14a,17a-benzylidenedioxy-4-androsten-3-one, isolated as anoil.

I.R. (in CHCl): u 1735, 1668, 1612 and 1585 cm.- N.M.R. (in CDCl 6:1.13,1.20, 5.75, 5.98 and 7.3-7.6

(multiplet) p.p.m. Highest mass number in mass spectrum:

Calculater for C H O I: 5.18. Found: 284 [according to molecularweight-(128+l06) (i.e. mol. weight HI+C H CHO) EXAMPLE VII (a) 2.5 g. of14a,17a-dihydroxyprogesterone were suspended in a mixture of 50 ml. ofacetaldehyde and 0.25 ml. of perchloric acid (70% the suspension wasstirred at room temperature. The steroid was completely dissolved within1 hour. To the reaction mixture 150ml. of methyl isobutyl ketone wereadded; the solution was neutralized with a solution of 1.5 g. of sodiumbicarbonate in 30 ml. of water. This solution was washed three timeswith water and the solvent was completely removed by destillation underreduced pressure. The residue was crystallized from a mixture (1: 1) ofacetone and water. Yield: 2.0 g. of 1411,17a-ethylidenedioxyprogesterone.

Melting point: 178181 C. N.M.R. (in CDCl;,): 6:0.83, 1.19, 1.36(doublet), 2.17,

5.16 (quadruplet) and 5.74 ppm. (b) A mixture of 0.5 ml. of triethylorthoformate, 0.03 g. of p-toluenesulphonic acid and 6.5 ml. of dioxanewas stirred at room temperature for 1 hour and then 1.0 g. of14a,17a-ethylidenedioxyprogesterone and 0.5 ml. of triethyl orthoformatewere added and the stirring was continued for 1 hour. The mixture wasthen neutralized with pyridine (0.8 ml.) and poured into 12 ml. of waterto give, as a crystalline precipitate, 0.9 g. of3-ethoxy-l4a,l7methylidenedioxy-3,5-pregnadiene-20-one.

Melting point: 146.5150 C. LR. (in CHCl v =1711, 1651, 1628, 1169 and1116 (c) 0.8 g. of 3-ethoxy-14a,17a-ethylidenedioxy-3,5-pregnadiene-ZO-one was added to a solution of 2.0 g. of hydroxylaminehydrochloride in 16 ml. of 5% sodium hydroxide solution in water;ethanol (48 ml.) was added until a clear solution was obtained. Thesolution was refiuxed for minutes, diluted with water and cooled. Yield:0.6 g. of 3-ethoxy-20-oximino-14a,17a-ethylidenedioxy-3,5-pregnadiene.

Melting point: 169-185 C. LR. (in CHCl v =3587, 1651, 1625, 1404, 1382,

1169 and 1114 cmr (d) A solution of 0.54 g. of 3-ethoxy-20-oximino-14oc,17u-ethylidenedioxy-3,5-pregnadiene in 30 ml. methanol was treated with0.3 ml. of 2 N hydrochloric acid and then refluxed for 10 minutes. Thesolution was diluted with 60 ml. of water and cooled in a refrigerator.Yield: 0.51 g. of crystalline 20 oximino 14u,l7m ethylidenedioxy-4-pregnene-3-one.

Melting point: 227-230 C. IR. (in CHCl v =3588, 1662, 1645, 1613 and1115 (e) A solution of 5 g. of20-oximino-14a,17u-ethylidenedioxy-4-pregnene-3-one in 20 ml. ofpyridine was treated slowly while stirred at 510 C. with a solution of10 ml. of phosphorous oxychloride in 30 ml. of pyridine and thenstirring was continued for 3 hours at room temperature. The mixture waspoured into ice water, neutralized with 4 N hydrochloric acid andextracted with chloroform. The extract was washed with water and driedon magnesium sulphate. Evaporation of the solvent yielded an oil, whichwas chromatographed on alumina, eluting with benzene/ ethyl acetate togive an oil which on crystallization from benzene, yield 3.2 g. of14u,17u-ethylidenedioxy-l7B-acetylarnino-4-andr0sten-3-0ne.

Melting point: l23125 C. I.R. (in CHCl v =3439, 1694, 1664, 1615, 1568,

1495 and 1113 cm.

(f) A mixture of 5.4 g. of :,l7oc-6thYlidGI16di0XY-17,6-acetylamino-4-androsten-3-one, ml. of acetic acid and 60 ml. ofacetic anhydride was treated with 16 g. of anhydrous potassium acetate,cooled to 7 C. and then 50 ml. of nitrosyl chloride in acetic anhydridewere added dropwise. The mixture was stirred for 2 hours at atemperature between 5 and 10 C. and then for 2 hours at roomtemperature. The reaction mixture was poured into ice water, neutralizedwith 4 N sodium hydroxide and extracted with chloroform. The extract wasdried on sodium sulphate and the solvent evaporated to give a residuewhich was triturated with 12 ml. of cold methanol. The crystallizedmaterial was filtered and washed with cold methanol to give 1.5 g. of14a-hydroxy-4-androsten-3,17- dione. The filtrate and the washings werecombined, the solvent evaporated and the residue chromatographed onalumina, eluting with benzene/ethyl acetate (2: 1) to give, as anamorphous solid, 1.1 g. of 14a,17ot-ethylidenedioxy-17B-acetoxy-4-androsten-3-one.

A (in methanol) :240 nm.; Ei'f =360 LR. (in CHCI u =l794, 1665, 1614,1406, 1369 and 1108 CHIS-1. N.M.R. (in CDCl ):5=1.00, 1.18, 1.33(doublet), 2.05,

5.20 (quadruplet) and 5.72 p.p.m. Molecular ion peak in mass spectrum:

Calculated for C H O 388. Found: 388.

EXAMPLE VII-I (a) According to the procedure described in Example VIIa,14a,17a-dihydroxyprogesterone was converted with n-pentanal to14a,17a-pentylidenedioxyprogesterone.

Melting point: 87.5 89 C. LR. (in CHCl u =1712, 1670, 1616, 1358 and1112 cmi- (b) According to the procedure described in Example VIlb,141x,l7a-pentylidenedioxyprogesterone was converted to3-ethoxy-l4a,17a-pentylidenedioxy-3,S-pregnadiene- 20-one.

Melting point: 8589 C. LR. (in CMCl v =l706, 1648, 1622, 1348 and 1108cmf (0) According to the procedure described in Example VIIc,3-ethoxy-14a,17a-pentylidenedioxy 3,5 pregnadiene-20-one was'convertedto 3-ethoxy-20-oximino-14a, 17a-pentylidenedioxy-3,S pregnadiene.

Melting point: l47 -150 C. LR. (in CHCl -v =3593, 1649, 1623, 1165 and1105 cmr Melting point: 91'92 C. LR. (in CMCl 11 ==3598, 166 5, 1613 and1107 cmr (e) .According to.v the procedure described in Example VIIe,20-oximino-14a,17a-pentylidenedioxy-4-pregnene-3- one was converted toamporphous 14a,17a-pentylidenedioxy-17,9-acetylamino-4-androsten-3-one.

LR. (in CHCl u =3440, 1709, 1665 and 1610 cmr- (f) According to theprocedure described in Example VIIf,14a,l7d-pentylidenedioxy-l7fi-acetylamino-4-androsten-3-one wasconverted to amorphous14a,17u-pentylidenedioxy-17fl-acetoxy-4-androstene-3-one.

A (in methanol)=242 nm.; E =325 LR. (in CHCl v =l750, 1662, 1612, 1362,1160,

1121, 1105, 1050, 1000, 938, 890 and 860 cmr N.M.R. (in CDCl 6:0.90(triplet), 1.00, 1.18, 2.05,

5.02 (triplet) and 5.75 p.p.m. Molecular ion peak in mass spectrum:

Calculated for C H O 430. Found: 430.

EXAMPLE IX (a) According to the procedure described in Example VIIa,14a,17u-dihydroxprogesterone was converted with benzaldehyde to14a,17a-benzylidenedioxyprogesterone.

Melting point: 182.5 1'85.5 C. IR. (in CHCI v =1715, 1668, 1620, 1452,1360 and 1020 cmr (b) According to the procedure described in ExampleVIIb, 14a,17a-benzylidenedioxyprogesterone was converted with trimethylorthoformate to3-methoxy-14a,17abenzylidenedioxy-3,S-pregnadiene-ZO-one.

Melting point: 136"-141 C. IR. (in CHCI v =2843, 1705, 1650, 1623 and1166 cmr (c) According to the procedure described in Example VIIc,3-methoxy 14a,17u benzylidenedioxy-3-5-pregnadiene-20-one was convertedto 3-1I16tl10XY-20-0Xifl1i1'10-14oc, 17abenzylidenedioxy-3,5-pregnadiene.

Melting point: 190-200 C. IR. (in CMCl v =3590, 2845, 1653, 1627, 1085and 983 cmr (d) According to the procedure described in Example VI-Id, 3methoxy-20-oximino-l4a,l7u-benzylidenedioxy- 3,5-pregnadiene wasconverted to 20OXiI11lIlO-140t,17otbenzylidenedioxy-4-pregnene-3-one.

Melting point: 238-243 C. IR. (in CHC1 v =3590, 1663, 1632, 1612, 1085and 985 cmr (e) According to the procedure described in Example VIIe,20-oximino-14a,17u-benzylidenedioxy 4 pregnene- 3-one was converted to14u,17a-benzylidenedioxy-17,8- acetylamino-4-androsten-3-one.

Melting point: 147.5150.5 C. LR. (in CHCl v =3433, 1740, 1698, 1668 and1613 cmf (f) According to the procedure described in Example VIIf,14a,17a-benzylidenedioxy-17,8-acety1amino-4-andro- 10 sten3-one wasconverted to 14u,17ot-benzylidenedioxy- 17,8-acetoxy-4-androsten-3-one.

Melting point: 113-116" C.

Am (in methanol)=240 nm.; E{'f',, =420 LR. (in CHCl 11 =1750, 1665, 1612and 136 8 cmf N.M.R. (in CDCl;;): 6:1.08, 1.22, 2.06, 5.74, 6.02 and7.47.6 (multiplet) p.p.m. Molecular ion peak in mass spectrum:

Calculated for C H O 450. Found: 450.

The invention includes with its scope pharmaceutical preparationscontaining, as the active ingredient, at least one of thetherapeutically active compounds of Formula 1 in association with apharmaceutically acceptable carrier. The preparations may take any ofthe forms customarily employed for administration of therapeuticallyactive substances but the preferred types are those suitable for oraladministration, especially tablets, including sustained release tablets,pills and capsules including the substance and those suitable forparenteral administration. The tablets and pills may be formulated inthe usual manner with one or more pharmaceutically acceptable diluentsor excipients, and include materials of a lubricating nature. Capsulesmade of absorbable material, such as gelatin, may contain the activesubstance alone or in a mixture, with a solid or liquid diluent. Liquidpreparations may be in the form of suspensions, emulsions, syrups orelixirs of the active substance in water or other liquid medium commonlyused for making orally acceptable pharmaceutical formulations.

The active substance may also be made up in a form suitable forparenteral administration, i.e. as a suspension or emulsion in sterileWater or an organic liquid usually employed for injectable preparations,for example a vegetable oil such as corn or olive oil, or a sterilesolution in water or an organic solvent.

For adult human therapy, the compounds may be administered orally indaily dosages such as tablets of 3 to 25 mg.; the compounds may also beadministered parenterally, subcutaneously or intramuscularly in the formof a depot preparation containing from 300 to 750 mg. of activesubstance, as a crystal suspension in Water of dissolved in a very pureoil, such as corn oil.

What we claim and desire to secure by letters patent is:

1. 14a,17a-methylenedioxy-androstane derivative of the formula wherein Rrepresents an aliphatic hydrocarbon group having less than 6 carbonatoms or a phenyl group and R represents an acetoxy group or a halogenatom.

2. 14a,17a-methylenedioxy derivative in accordance with claim 1 whereinsaid derivative is 14cx,l7a-ethylidenedioxy-l7B-acetoxy-4-androsten-3-one.

3. l4a,l7a-methylenedioxy derivative in accordance with claim 1 whereinsaid derivative is14a,17a-pentylidenedioxy-l7/3-acetoxy-4-androsten-3-one.

4. 14a,17a-methylenedioxy in accordance with claim 1 wherein saidderivative is 14a,l7a-benzylidenedioxy-17,8- acetoxy-4-androsten-3-one.

5. 14u,17a-methylenedioxy derivative in accordance with claim 1 whereinsaid derivative is17B-ChlOIO-l4ot,l7otethylidenedioXy-4-androstem-3-one.

6. 14a,17a-methylenedioxy derivative in accordance with claim 1 whereinsaid derivative is 17,8-chlor0-14a,l7ahexylidenedioxy-4-androsten-3-one.

7. l4u,l7u-methylenedioxy derivative in accordance OCHR with claim 1wherein said derivative is 17B-ChlOIO-14oz,17ocbenzylidenedioxy-4-androsten-3-one.

8. l4u,l7a-methylenedioxy derivative in accordance with claim 1 whereinsaid derivative is 17B-i0d0-14a,l7 xethylidenedioxy-4-androsten-3-one.

9. l4a,l7a-methylenedioxy derivative in accordance with claim 1 whereinsaid derivative is 17fl-iOdO-l4a,l7ozheXylidenedioxy-4-androsten-3-one.

10. 14a,17a-methylenedioxy derivative in accordance with claim 1 whereinsaid derivative is 17 3-i0d014a,17xbenzylidenedioxy-4-androsten-3-0ne.

11. 3 alkoxy 140:,170: methylenedioxy-3,S-pregnadiene-ZO-oximinoderivative of the formula wherein R represents an aliphatic hydrocarbonhaving 25 less than 6 carbon atoms or a phenyl group and R represents analkyl group having less than 5 carbon atoms.

wherein R represents an aliphatic hydrocarbon having 15 less than 6carbon atoms or a phenyl group.

References Cited FOREIGN PATENTS 6703781 9/1968 Netherlands.

ELBERT L. ROBERTS, Primary Examiner E. G. LOVE, Assistant Examiner US.Cl. X.R.

